Bottom Line:
The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor.Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism.In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.

Background: The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism.

Scope of review: In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery.

Major conclusions: In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.

fig3: Milestones in ghrelin research. Bar graph represents the number of publications listed in the US National Library of Medicine National Institute of Health (PubMed) and that contain the word ‘ghrelin’ in either the title or the abstract until December 2014.

Mentions:
The discovery of GOAT as the enzyme responsible for ghrelin acylation [56,57] has been a major breakthrough for understanding the role that acyl-modification plays in ghrelin's physiology (Figure 3). This modification, mainly octanoylation and, to a lesser extent, decanoylation, is required for ghrelin's effects on systemic metabolism. The data demonstrating GOAT's essential role in the activation of ghrelin are clear. First, GOAT and des-acyl ghrelin are sufficient to recapitulate the production of acyl-modified ghrelin in cells that normally do not express either of these gene products [56,57]. Second, ghrelin and GOAT share a similar tissue expression profiles in both humans and mice with highest GOAT expression in pancreas and stomach in humans and the stomach and intestine in mice [56,58,59]. Third, GOAT, like ghrelin, is highly conserved across vertebrates. Humans, rats, mice, and zebrafish all exhibit functional GOAT activity, and sequences with amino acid similarities to GOAT are present in other vertebrates, consistent with the presence of octanoylated forms of ghrelin across vertebrates [56]. Finally, the most convincing data for GOAT as ghrelin's acyl transferase are from GOAT-deficient mice, which completely lack octanoyl and decanoyl modified forms of ghrelin [20,56,60–62].

fig3: Milestones in ghrelin research. Bar graph represents the number of publications listed in the US National Library of Medicine National Institute of Health (PubMed) and that contain the word ‘ghrelin’ in either the title or the abstract until December 2014.

Mentions:
The discovery of GOAT as the enzyme responsible for ghrelin acylation [56,57] has been a major breakthrough for understanding the role that acyl-modification plays in ghrelin's physiology (Figure 3). This modification, mainly octanoylation and, to a lesser extent, decanoylation, is required for ghrelin's effects on systemic metabolism. The data demonstrating GOAT's essential role in the activation of ghrelin are clear. First, GOAT and des-acyl ghrelin are sufficient to recapitulate the production of acyl-modified ghrelin in cells that normally do not express either of these gene products [56,57]. Second, ghrelin and GOAT share a similar tissue expression profiles in both humans and mice with highest GOAT expression in pancreas and stomach in humans and the stomach and intestine in mice [56,58,59]. Third, GOAT, like ghrelin, is highly conserved across vertebrates. Humans, rats, mice, and zebrafish all exhibit functional GOAT activity, and sequences with amino acid similarities to GOAT are present in other vertebrates, consistent with the presence of octanoylated forms of ghrelin across vertebrates [56]. Finally, the most convincing data for GOAT as ghrelin's acyl transferase are from GOAT-deficient mice, which completely lack octanoyl and decanoyl modified forms of ghrelin [20,56,60–62].

Bottom Line:
The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor.Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism.In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.

Background: The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism.

Scope of review: In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery.

Major conclusions: In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.